Cigarette smoking and alcohol misuse rank among the foremost public health problems facing the United States. Understanding the biological mechanisms underlying smoking and drinking is integral to designing targeted and effective treatment strategies. Given the high occurrence of heavy alcohol drinking and cigarette smoking, and the increased number of young, college- age binge drinkers, we plan to elucidate some of the opioidergic mechanisms of reinforcement of co-existing alcohol and nicotine use. Alcohol and nicotine effect hypothalamic-pituitary-adrenal (HPA) axis function, however, little is known about the possible interactions between nicotine and alcohol in these effects. Work in our laboratory and in others has shown that the endogenous opioid system has a role in the regulatory control and release of HPA axis hormones, which in turn may relate to the initiation, maintenance, and relapse to heavy use of addicting substances. Our first aim is to study HPA activity and subjective factors related to smoking behaviors in the following three groups of regular heavy smokers, with different drinking histories, while they smoke: Group 1 - recently sober alcoholics; Group 2 - binge/heavy consumption social drinkers; and Group 3 - light social drinkers. Non-smoking light social drinkers, who will not smoke, Group 4, will serve as a control group. Adjunctive treatment with opioid antagonists has been shown to reduce alcohol intake and relapse rates in alcohol-dependent persons, through parallel data in nicotine-dependant persons are mixed. Our second aim, therefore, is to study the effects of a preadministered bolus of the mu-selective but also kappa-directed opioid antagonist nalmefene on HPA activity and subjective measures in the above four groups. By elucidating the role of the stress- responsive endogenous opioid system in smokers with different drinking patterns, we may begin to understand the combined reinforcing properties of heave use and abuse of both substances, which may ultimately lead to the identification of and improved pharmacologic treatments strategies for subgroups most likely to benefit.